Mannheimia haemolytica (previously known as Pasteurella haemolytica) is a weakly hemolytic, gram-negative coccobacillus that is an opportunistic pathogen of cattle, sheep and other ruminants. Pasteurellosis kills at least one percent of North American feedlot cattle and is responsible for morbidity, decreased weight gain and loss of performance in at least an additional ten percent of these animals. Consequently, the disease costs the United States cattle industry nearly a billion dollars annually. It is also a common disease of sheep, where outbreaks are also associated with management practices such as overcrowding and transport. M. haemolytica is also a prevalent cause of ovine mastitis in the United Kingdom. In addition, it can cause disease other ruminants, including goats, bison, and bighorn sheep.

Mannheimia haemolytica is a member of the gamma subdivision of the Proteobacteria in the family Pasteurelleaceae, commonly called the Haemophilus, Actinobacillus, and Pasteurella (HAP) family. Haemophilus ducreyii is most closely related to M. haemolytica based on 16S rRNA sequences. Eleven serotypes (1, 2, 5, 6, 7, 8, 9, 12, 13, 14, and 16), originally known as biotype A, are included in the species. Worldwide, ST1 and ST2 are the most prevalent serotypes found: ST1 is recognized as the most common cause of pasteurellosis in cattle, but other serotypes are occasionally associated with disease; ST2 causes disease in sheep, but it is also a predominant member of the upper respiratory tract (URT) flora of healthy calves. The strain being sequenced, strain PHL213, is an ST1 strain isolated from the lung of a pneumonic calf.

Exotoxins which belong to the family containing the RTX toxins (repeats in toxin) contribute to a variety of important human and animal diseases. One example of such a toxin is the potent leukotoxin (LKT) produced by the bovine respiratory pathogen Mannheimia haemolytica. LKT binds to CD18, resulting in the death of bovine leukocytes. In this study, we showed that internalized LKT binds to the outer mitochondrial membrane, which results in the release of cytochrome c and collapse of the mitochondrial membrane potential (psi(m)). Incubation of bovine lymphoblastoid cells (BL-3 cells) with the mitochondrial membrane-stabilizing agent cyclosporine (CSA) reduced LKT-mediated cytotoxicity, cytochrome c release, and collapse of the psi(m). Coimmunoprecipitation and intracellular binding studies suggested that LKT binds to the mitochondrial matrix protein cyclophilin D. We also demonstrated that LKT mobilizes the vesicle scission protein dynamin-2 from mitochondria to the cell membrane. Incubation with CSA depleted mitochondrial dynamin-2 in BL-3 cells, making it unavailable for vesicle scission and LKT internalization. The results of this study show that LKT trafficking and LKT-mediated cell death involve dynamin-2 and cyclophilin D, in a process that can be prevented by the mitochondrial membrane-protecting function of CSA.